Peripheral neuropathy is a major clinical problem that afflicts about 20 million persons in the U.S. alone. Pain is a prominent feature and it is generally stubbornly resistant to treatment. Our preliminary data have shown that transection of the 5th lumbar ventral root (L5 Ventral Rhizotomy) in rat results in pain behavior, altered C-fiber electrophysiology, and changes in C-fiber cell biology. In the L5 Ventral Rhizotomy model of neuropathic pain, C-fiber sensory axons are not directly injured but respond briskly to degeneration of nearby motor axons. The degenerating and uninjured axons co-mingle in peripheral nerve but do not interact directly in the spinal cord, sensory ganglion or skin. Our central hypothesis is: Degenerating axons in the peripheral nerve signal uninjured C-fibers via diffusible factors and that this leads to neuropathic pain. SPECIFIC AIM 1 is to determine the role of peripheral nerve interactions between uninjured and degenerating axons in neuropathic pain behavior. This will be studied using a newly developed model of neuropathic pain that implants a degenerating nerve segment from an inbred donor over a fenestration in the sciatic nerve of a recipient animal. A complementary approach will be taken by minimizing peripheral nerve interactions using L3 ventral rhizotomy;in general, L3 axons do not enter the sciatic nerve. SPECIFIC AIM 2 is to examine the response of uninjured C-fibers to degenerating axons in peripheral nerve using these same models. The responses of uninjured C-fibers will be measured as changes in C-fiber conduction velocity properties and increased mitosis of nonmyelinating Schwann cells. SPECIFIC AIM 3 will assess the role of NGF, as a potential diffusible factor released after nerve injury that is responsible for pain behavior and neuropathic C-fiber change. This will be studied by translating the above methods into mouse species and studying the responses to these same models in a strain of mice that has inducible inhibition of signaling through the TrkA, high-affinity NGF receptor. The long term objectives of this research are to identify therapeutic targets for the treatment of neuropathic pain. This research will be conducted during a period of mentored career development emphasizing advanced skills in pain research and the responsible conduct of science.